PROJECT SUMMARY/ABSTRACT My Outstanding Investigator Award (OIA) research plan will build on themes developed during my more than three decades of RAS research, pursuing directions generally ignored by the RAS field and by the NCI RAS Initiative, to make ?undruggable? RAS druggable. I was a member of the research team that made the initial identification of activated RAS oncogenes in human cancers. Since that discovery, my research has centered on understanding the basic biochemistry, signaling and biology of RAS proteins, with the long-term goal of utilizing that information for the development of anti-RAS cancer therapies. My research focuses on pancreatic ductal adenocarcinoma (PDAC), a cancer where effective targeted therapies remain to be found. With a 95% KRAS mutation frequency and with substantial experimental evidence that ?correcting? the KRAS defect will significantly impair PDAC growth, PDAC is arguably the most RAS-addicted cancer. The OIA supports research that ?take[s] greater risks, [is] more adventurous?. Based on our unpublished findings from studies initiated 3-4 years ago and just now coming into fruition, I have identified four new high risk / high reward research directions. First, despite the well-established interdependency between the RAS and MYC oncogenes in driving cancer growth, targeting MYC as an anti-KRAS strategy is not widely considered. Our MYC degradation screen identified novel protein kinases that regulate MYC protein stability; we will exploit these to cause MYC loss. Second, we have found that the ERK protein kinases are largely responsible for KRAS-dependent metabolic perturbations (autophagy, glycolysis, macropinocytosis, mitochondrial function). We suggest that targeting ERK, rather than the metabolic enzymes considered by the field, will be a more effective therapeutic strategy to target cancer metabolism. We will pursue an issue still largely neglected, the determination of the key ERK substrates that are critical for ERK-dependent KRAS-mutant PDAC growth. Third, as with other targeted therapies, anti-KRAS therapies will be limited by mechanisms of acquired resistance. While much of the field is focused on YAP1, it is also clear that YAP1-independent mechanisms will also play significant role in how cancers escape KRAS-dependency. We will apply experimental approaches not previously utilized to define these YAP1?independent mechanisms. These findings will be critical for development of anti-KRAS therapies that can achieve long-lasting clinical efficacy. Finally, our surprising finding that one KRAS mutant (G12R) cannot utilize a key RAS effector, PI3K, and drives metabolic activities distinct from the most prevalent KRAS mutations, provides our rationale to pursue outlier mutations in PDAC, to identify mutation-specific vulnerabilities as the basis for development of mutation-selective therapies. In summary, since adherence to long-held dogma has at times stifled progress, less mainstream directions must be taken if we are to finally achieve the breakthroughs needed for development of effective anti-RAS therapies.